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  • 1.
    Anderl, Ines
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Laboratory of Genetic Immunology, BioMediTech, University of Tampere, Tampere, Finland.
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Laboratory of Genetic Immunology, BioMediTech, University of Tampere, Tampere, Finland.
    New ways to make a blood cell2015In: eLIFE, E-ISSN 2050-084X, Vol. 4, e06877Article in journal (Other academic)
  • 2. Brey, Paul T.
    et al.
    Hultmark, DanUmeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Molecular mechanisms of immune responses in insects.1998Collection (editor) (Other academic)
  • 3. Choe, Kwang-Min
    et al.
    Werner, Thomas
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Stöven, Svenja
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Anderson, Kathryn V.
    Requirement of a peptidoglycan recognition protein (PGRP) in Relish activation and antimicrobial immune responses in Drosophila.2002In: Science, Vol. 296, no 12 April 2002, 359-362 p.Article in journal (Refereed)
  • 4. Drosophila 12 Genomes Consortium,
    et al.
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Evolution of genes and genomes on the Drosophila phylogeny.2007In: Nature, ISSN 1476-4687, Vol. 450, no 7167, 203-18 p.Article in journal (Refereed)
    Abstract [en]

    Comparative analysis of multiple genomes in a phylogenetic framework dramatically improves the precision and sensitivity of evolutionary inference, producing more robust results than single-genome analyses can provide. The genomes of 12 Drosophila species, ten of which are presented here for the first time (sechellia, simulans, yakuba, erecta, ananassae, persimilis, willistoni, mojavensis, virilis and grimshawi), illustrate how rates and patterns of sequence divergence across taxa can illuminate evolutionary processes on a genomic scale. These genome sequences augment the formidable genetic tools that have made Drosophila melanogaster a pre-eminent model for animal genetics, and will further catalyse fundamental research on mechanisms of development, cell biology, genetics, disease, neurobiology, behaviour, physiology and evolution. Despite remarkable similarities among these Drosophila species, we identified many putatively non-neutral changes in protein-coding genes, non-coding RNA genes, and cis-regulatory regions. These may prove to underlie differences in the ecology and behaviour of these diverse species.

  • 5.
    Ekengren, Sophia
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    A family of Turandot-related genes in the humoral stress response of Drosophila.2001In: Biochem Biophys Res Commun, ISSN 0006-291X, Vol. 284, no 4, 998-1003 p.Article in journal (Refereed)
    Abstract [en]

    The Drosophila Turandot A (TotA) gene was recently shown to encode a stress-induced humoral factor which gives increased resistance to the lethal effects of high temperature. Here we show that TotA belongs to a family of eight Tot genes distributed at three different sites in the Drosophila genome. All Tot genes are induced under stressful conditions such as bacterial infection, heat shock, paraquat feeding or exposure to ultraviolet light, suggesting that all members of this family play a role in Drosophila stress tolerance. The induction of the Tot genes differs in important respects from the heat shock response, such as the strong but delayed response to bacterial infection seen for several of the genes.

  • 6.
    Ekengren, Sophia
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Drosophila cecropin as an antifungal agent.1999In: Insect Biochem Mol Biol, ISSN 0965-1748, Vol. 29, no 11, 965-72 p.Article in journal (Refereed)
    Abstract [en]

    The effects of Drosophila and Hyalophora cecropins were tested against different fungi, both insect pathogens and fungi from the normal environment of Drosophila. The fungi were generally found to be as susceptible to the cecropins as most bacteria, the only exception being the insect pathogen Beauveria bassiana which is completely resistant. This is also the only fungus tested which is virulent to Drosophila, giving 100% lethality within 5 days after injection. Lethal concentrations of cecropins against other fungi tested ranged between 0.4 and 4 microM. Andropin is less fungicidal than the cecropins, and Drosophila cecropin A is somewhat more potent than cecropin B. Even dense cultures of Saccharomyces cerevisiae can be cleared by micromolar concentrations of cecropin, whereas Geotrichum candidum is unaffected by cecropin when tested in a dense culture.

  • 7.
    Ekengren, Sophia
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Tryselius, Ylva
    Dushay, Mitchell S
    Liu, Gang
    Steiner, Håkan
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    A humoral stress response in Drosophila.2001In: Curr Biol, ISSN 0960-9822, Vol. 11, no 9, 714-8 p.Article in journal (Refereed)
    Abstract [en]

    The ability to react to unfavorable environmental changes is crucial for survival and reproduction, and several adaptive responses to stress have been conserved during evolution [1-3]. Specific immune and heat shock responses mediate the elimination of invading pathogens and of damaged proteins or cells [4-6]. Furthermore, MAP kinases and other signaling factors mediate cellular responses to a very broad range of environmental insults [7-9]. Here we describe a novel systemic response to stress in Drosophila. The Turandot A (TotA) gene encodes a humoral factor, which is secreted from the fat body and accumulates in the body fluids. TotA is strongly induced upon bacterial challenge, as well as by other types of stress such as high temperature, mechanical pressure, dehydration, UV irradiation, and oxidative agents. It is also upregulated during metamorphosis and at high age. Strikingly, flies that overexpress TotA show prolonged survival and retain normal activity at otherwise lethal temperatures. Although TotA is only induced by severe stress, it responds to a much wider range of stimuli than heat shock genes such as hsp70 or immune genes such as Cecropin A1.

  • 8.
    Ekström, Jens-Ola
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Habayeb, Mazen S
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Srivastava, Vaibhav
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Kieselbach, Thomas
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Wingsle, Gunnar
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Drosophila Nora virus capsid proteins differ from those of other picorna-like viruses2011In: Virus Research, ISSN 0168-1702, E-ISSN 1872-7492, Vol. 160, no 1-2, 51-58 p.Article in journal (Refereed)
    Abstract [en]

    The recently discovered Nora virus from Drosophila melanogaster is a single-stranded RNA virus. Its published genomic sequence encodes a typical picorna-like cassette of replicative enzymes, but no capsid proteins similar to those in other picorna-like viruses. We have now done additional sequencing at the termini of the viral genome, extending it by 455 nucleotides at the 5' end, but no more coding sequence was found. The completeness of the final 12,333-nucleotide sequence was verified by the production of infectious virus from the cloned genome. To identify the capsid proteins, we purified Nora virus particles and analyzed their proteins by mass spectrometry. Our results show that the capsid is built from three major proteins, VP4A, B and C, encoded in the fourth open reading frame of the viral genome. The viral particles also contain traces of a protein from the third open reading frame, VP3. VP4A and B are not closely related to other picorna-like virus capsid proteins in sequence, but may form similar jelly roll folds. VP4C differs from the others and is predicted to have an essentially α-helical conformation. In a related virus, identified from EST database sequences from Nasonia parasitoid wasps, VP4C is encoded in a separate open reading frame, separated from VP4A and B by a frame-shift. This opens a possibility that VP4C is produced in non-equimolar quantities. Altogether, our results suggest that the Nora virus capsid has a different protein organization compared to the order Picornavirales.

  • 9.
    Ekström, Jens-Ola
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). BioMediTech, FI-33014 University of Tampere, Finland.
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). BioMediTech, FI-33014 University of Tampere, Finland.
    A Novel Strategy for Live Detection of Viral Infection in Drosophila melanogaster2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, 26250Article in journal (Refereed)
    Abstract [en]

    We have created a transgenic reporter for virus infection, and used it to study Nora virus infection in Drosophila melanogaster. The transgenic construct, Munin, expresses the yeast transcription factor Gal4, tethered to a transmembrane anchor via a linker that can be cleaved by a viral protease. In infected cells, liberated Gal4 will then transcribe any gene that is linked to a promoter with a UAS motif, the target for Gal4 transcription. For instance, infected cells will glow red in the offspring of a cross between the Munin stock and flies with a UAS-RFPnls transgene (expressing a red fluorescent protein). In such flies we show that after natural infection, via the faecal-oral route, 5-15% of the midgut cells are infected, but there is little if any infection elsewhere. By contrast, we can detect infection in many other tissues after injection of virus into the body cavity. The same principle could be applied for other viruses and it could also be used to express or suppress any gene of interest in infected cells.

  • 10. Evans, J D
    et al.
    Aronstein, K
    Chen, Y P
    Hetru, C
    Imler, J-L
    Jiang, H
    Kanost, M
    Thompson, G J
    Zou, Z
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Immune pathways and defence mechanisms in honey bees Apis mellifera.2006In: Insect Mol Biol, ISSN 0962-1075, Vol. 15, no 5, 645-56 p.Article in journal (Refereed)
    Abstract [en]

    Social insects are able to mount both group-level and individual defences against pathogens. Here we focus on individual defences, by presenting a genome-wide analysis of immunity in a social insect, the honey bee Apis mellifera. We present honey bee models for each of four signalling pathways associated with immunity, identifying plausible orthologues for nearly all predicted pathway members. When compared to the sequenced Drosophila and Anopheles genomes, honey bees possess roughly one-third as many genes in 17 gene families implicated in insect immunity. We suggest that an implied reduction in immune flexibility in bees reflects either the strength of social barriers to disease, or a tendency for bees to be attacked by a limited set of highly coevolved pathogens.

  • 11.
    Habayeb, Mazen
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Cantera, Rafael
    Zoology Department, Stockholm University, Instituto de Investigaciones Biológicas Clemente Estable, Av. Italia, 3318 Montevideo, Uruguay.
    Casanova, Gabriela
    Department of Cell and Molecular Biology, Transmission Electron Microscopy Unit, Faculty of Sciences, Montevideo, Uruguay.
    Ekström, Jens-Ola
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Albright, Shannon
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    The Drosophila Nora virus is an enteric virus, transmitted via feces2009In: Journal of Invertebrate Pathology, ISSN 0022-2011, E-ISSN 1096-0805, Vol. 101, 29-33 p.Article in journal (Refereed)
    Abstract [en]

     The biology of the Drosophila viruses has not been intensely investigated. Here we have investigated the biology of the Nora virus, a persistent Drosophila virus. We find that injected Nora virus is able to replicate in the files, reaching a high titer that is maintained in the next generation. There is a remarkable variation in the viral loads of individual flies in persistently infected stocks; the titers can differ by three orders of magnitude. The Nora virus is mainly found in the intestine of infected flies, and the histology of these infected intestines show increased vacuolization. The virus is excreted in the feces and is horizontally transmitted. The Nora virus infection has a very mild effect on the longevity of the flies, and no significant effect on the number of eggs laid and the percent of eggs that develop to adults.

  • 12.
    Habayeb, Mazen
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Ekengren, Sophia
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Nora virus, a persistent virus in Drosophila, defines a new picorna-like virus family.2006In: Journal of General Virology, ISSN 0022-1317, E-ISSN 1465-2099, Vol. 87, no Pt 10, 3045-3051 p.Article in journal (Refereed)
    Abstract [en]

    Several viruses, including picornaviruses, are known to establish persistent infections, but the mechanisms involved are poorly understood. Here, a novel picorna-like virus, Nora virus, which causes a persistent infection in Drosophila melanogaster, is described. It has a single-stranded, positive-sense genomic RNA of 11879 nt, followed by a poly(A) tail. Unlike other picorna-like viruses, the genome has four open reading frames (ORFs). One ORF encodes a picornavirus-like cassette of proteins for virus replication, including an iflavirus-like RNA-dependent RNA polymerase and a helicase that is related to those of mammalian picornaviruses. The three other ORFs are not closely related to any previously described viral sequences. The unusual sequence and genome organization in Nora virus suggest that it belongs to a new family of picorna-like viruses. Surprisingly, Nora virus could be detected in all tested D. melanogaster laboratory stocks, as well as in wild-caught material. The viral titres varied enormously, between 10(4) and 10(10) viral genomes per fly in different stocks, without causing obvious pathological effects. The virus was also found in Drosophila simulans, a close relative of D. melanogaster, but not in more distantly related Drosophila species. It will now be possible to use Drosophila genetics to study the factors that control this persistent infection.

  • 13.
    Habayeb, Mazen S
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Ekström, Jens-Ola
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Nora virus persistent infections are not affected by the RNAi machinery.2009In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 4, no 5, e5731- p.Article in journal (Refereed)
    Abstract [en]

    Drosophila melanogaster is widely used to decipher the innate immune system in response to various pathogens. The innate immune response towards persistent virus infections is among the least studied in this model system. We recently discovered a picorna-like virus, the Nora virus which gives rise to persistent and essentially symptom-free infections in Drosophila melanogaster. Here, we have used this virus to study the interaction with its host and with some of the known Drosophila antiviral immune pathways. First, we find a striking variability in the course of the infection, even between flies of the same inbred stock. Some flies are able to clear the Nora virus but not others. This phenomenon seems to be threshold-dependent; flies with a high-titer infection establish stable persistent infections, whereas flies with a lower level of infection are able to clear the virus. Surprisingly, we find that both the clearance of low-level Nora virus infections and the stability of persistent infections are unaffected by mutations in the RNAi pathways. Nora virus infections are also unaffected by mutations in the Toll and Jak-Stat pathways. In these respects, the Nora virus differs from other studied Drosophila RNA viruses.

  • 14.
    Hedengren, Marika
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Borge, Karin
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Expression and evolution of the Drosophila attacin/diptericin gene family.2000In: Biochem Biophys Res Commun, ISSN 0006-291X, Vol. 279, no 2, 574-81 p.Article in journal (Refereed)
    Abstract [en]

    We describe the genes for three new glycine-rich antimicrobial peptides in Drosophila, two attacins (AttC and AttD) and one diptericin (DptB). Their structures support the proposal that these glycine-rich antimicrobial peptides evolved from a common ancestor and are probably also related to proline-rich peptides such as drosocin. AttC is similar to the nearby AttA and AttB genes. AttD is more divergent and located on a different chromosome. Intriguingly, AttD may encode an intracellular attacin. DptB is linked in tandem to the closely related Diptericin. However, the DptB gene product contains a furin-like cleavage site and may be processed in an attacin-like fashion. All attacin and diptericin genes are induced after bacterial challenge. This induction is reduced in imd mutants, and unexpectedly also in Tl(-) mutants. The 18w mutation particularly affects the induction of AttC, which may be a useful marker for 18w signaling.

  • 15.
    Hedengren, Marika
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Åsling, Bengt
    Dushay, Mitchell S
    Ando, Istvan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Ekengren, Sophia
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Wihlborg, Margareta
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Relish, a central factor in the control of humoral but not cellular immunity in Drosophila.1999In: Mol Cell, ISSN 1097-2765, Vol. 4, no 5, 827-37 p.Article in journal (Refereed)
    Abstract [en]

    The NF-kappa B-like Relish gene is complex, with four transcripts that are all located within an intron of the Nmdmc gene. Using deletion mutants, we show that Relish is specifically required for the induction of the humoral immune response, including both antibacterial and antifungal peptides. As a result, the Relish mutants are very sensitive to infection. A single cell of E. cloacae is sufficient to kill a mutant fly, and the mutants show increased susceptibility to fungal infection. In contrast, the blood cell population, the hematopoietic organs, and the phagocytic, encapsulation, and melanization responses are normal. Our results illustrate the importance of the humoral response in Drosophila immunity and demonstrate that Relish plays a key role in this response.

  • 16. Honeybee Genome Sequencing Consortium, the
    et al.
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Insights into social insects from the genome of the honeybee Apis mellifera.2006In: Nature, ISSN 1476-4687, Vol. 443, no 7114, 931-49 p.Article in journal (Refereed)
    Abstract [en]

    Here we report the genome sequence of the honeybee Apis mellifera, a key model for social behaviour and essential to global ecology through pollination. Compared with other sequenced insect genomes, the A. mellifera genome has high A+T and CpG contents, lacks major transposon families, evolves more slowly, and is more similar to vertebrates for circadian rhythm, RNA interference and DNA methylation genes, among others. Furthermore, A. mellifera has fewer genes for innate immunity, detoxification enzymes, cuticle-forming proteins and gustatory receptors, more genes for odorant receptors, and novel genes for nectar and pollen utilization, consistent with its ecology and social organization. Compared to Drosophila, genes in early developmental pathways differ in Apis, whereas similarities exist for functions that differ markedly, such as sex determination, brain function and behaviour. Population genetics suggests a novel African origin for the species A. mellifera and insights into whether Africanized bees spread throughout the New World via hybridization or displacement.

  • 17.
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Drosophila immunity: paths and patterns.2003In: Curr Opin Immunol, ISSN 0952-7915, Vol. 15, no 1, 12-9 p.Article, review/survey (Other (popular science, discussion, etc.))
    Abstract [en]

    Flies respond to infection with both humoral and cellular immune defenses, including a powerful set of inducible peptide antibiotics as well as actively proliferating and differentiating blood cells. The system that activates these responses is related to that of the innate immune defense in humans. A key role in Drosophila immunity is played by the recently discovered peptidoglycan recognition proteins. These pattern recognition molecules relay signals via two main signaling pathways. The imd/Relish pathway is responsible for the main part of the humoral response. The Toll/Dif pathway activates the blood cells and induces the antifungal peptide Drosomycin.

  • 18.
    Hultmark, Dan
    Stockholms universitet, mikrobiologiska institutionen.
    Insect immunity: Inducible antibacterial proteins from Hyalophora cecropia1982Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    A powerful bactericidal activity can be induced in the hemolymph of many insects as a response to an injection of bacteria. The nature of the effector molecules of this immune response was investigated, using pupae of the Cecropia moth, Hyalophora cecropia. Three major types of antibacterial proteins were found: the cecropins, the P5 proteins, and lysozyme. They appear in the hemolymph as a result of de novo synthesis.Six different cecropins were purified and characterized. The full amino acid sequences of the three major cecropins A, B and D were determined, as well as partial sequences of the three minor cecropins C, E and F. The cecropins are all very small (Mr = 4,000) and basic (pI > 9.5) proteins, and they show extensive homology in their sequences. The three major cecropins are products of different genes. Their C-terminals are blocked by uncharged groups, which can be removed by mild acid hydrolysis. The minor cecropins are closely related to the major forms, and may be unblocked precursors or, in one case (cecropin F), a minor allelic form. The cecropins were shown to be lytic, and to be efficient against several Gram positive and Gram negative bacterial strains, but not against mammalian cells.The P5 proteins are bactericidal proteins, larger than the cecropins (Mr = 20,000 - 23,000). Six forms, differing in isoelectric point, were isolated. They form two closely related groups, the basic (P5 A-D) and the acidic forms (P5 E-F). Within each group, the different forms have almost identical amino acid compositions.The Cecropia lysozyme is similar to lysozymes isolated from other insects, as well as to that from hen egg white. It is lytic to a restricted number of Gram positive bacteria.The presence of cecropins and other antibacterial factors was demon-strated also in other lepidopterans, notably Galleria mellonella, and may explain earlier observations of antibacterial factors in the latter species.

  • 19.
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Model organism immunology: What flies can tell us about immunity2000In: J. Leukoc. Biol., Vol. 57, no Suppl S, 19-19 p.Article in journal (Other academic)
  • 20.
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Quantification of antimicrobial activity, using the inhibition-zone assay1998In: Techniques in insect immunology, SOS Publications, Fair Haven , 1998, 103-107 p.Chapter in book (Other academic)
    Abstract [en]

    One of the most popular antimicrobial assays is based on the simple principle that the sample is applied on a bacterial plate, seeded with bacteria or fungi. The effect is recorded as a zone of inhibited bacterial growth. This assay will here be referred to as the inhibition-zone assay.

  • 21.
    Hultmark, Dan
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Borge Renberg, Karin
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Drosophila immunity: is antigen processing the first step?2007In: Curr Biol, ISSN 0960-9822, Vol. 17, no 1, R22-4 p.Article in journal (Refereed)
    Abstract [en]

    A new genetic study has shown that the phagocytic ability of Drosophila blood cells, the hemocytes, may be important for the further induction of an antibacterial response in other tissues.

  • 22.
    Hultmark, Dan
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Ekengren, Sophia
    A cytokine in the Drosophila stress response.2003In: Dev Cell, ISSN 1534-5807, Vol. 5, no 3, 360-1 p.Article in journal (Refereed)
    Abstract [en]

    The fruit fly, Drosophila melanogaster, has become a popular tool for studying immediate reactions to environmental hazards, such as the heat shock and innate immune responses. In mammals, protective responses to infections and other insults are coordinated by a complex network of cytokines that mediate cell-to-cell signaling. By contrast, the corresponding heat shock and innate immune responses in Drosophila have usually been regarded as cell-autonomous processes. However, in this issue of Developmental Cell, show that cytokines do play a role in mediating an acute phase response in this organism.

  • 23. István, Andó
    et al.
    Barbara, Laurinyecz
    István, Nagy
    Róbert, Márkus
    Rus, Florentina
    Balázs, Váczi
    Lános, Zsámboki
    László, Fehér
    Gateff, Elisabeth
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Kurucz, Éva
    Our archaic heritage: the innate immunity. The cellular immunity of Drosophila [Ösi örökségünk: a veleszületett immunitás. A Drosophila sejtes immunitása]2003In: Magyar Immunológia, Vol. 2, no 4, 39-45 p.Article in journal (Refereed)
    Abstract [en]

    Authors describe the essentials of the cellular immunity of Drosophila. They describe the Drosophila CD system, the main blood cell lineages and a blood cell differentiation model based on the expression of the CD antigens.

  • 24.
    Keyser, Pia
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Borge Renberg, Karin
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    The Drosophila NFAT homolog is involved in salt stress tolerance.2007In: Insect Biochem Mol Biol, ISSN 0965-1748, Vol. 37, no 4, 356-62 p.Article in journal (Refereed)
    Abstract [en]

    The NFAT gene encodes the only homolog in Drosophila of the five human Nuclear Factors of Activated T-cells, NFAT1-5. Its rel homology domain is most similar to that of NFAT5, and like the latter it lacks conserved AP1 and calcineurin binding sites. Two promoters give rise to alternative transcripts that are ubiquitously expressed in several different tissues. We generated mutants for each transcript, as well as a mutant that lacks all functional NFAT expression. Only the null mutant generated a visible phenotype, indicating that the two transcripts are redundant. The mutants are sensitive to high salt diet and have enlarged anal pads in hypotonic solution, suggesting that NFAT, like mammalian NFAT5, is regulating the osmotic balance. A phylogenetic reconstruction puts the Drosophila gene near the root of the NFAT tree, indicating that regulation of tonicity may be an ancestral function of the NFAT family.

  • 25. Kleino, Anni
    et al.
    Myllymäki, Henna
    Kallio, Jenni
    Vanha-aho, Leena-Maija
    Oksanen, Kaisa
    Ulvila, Johanna
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Valanne, Susanna
    Rämet, Mika
    Pirk is a negative regulator of the Drosophila Imd pathway.2008In: J Immunol, ISSN 0022-1767, Vol. 180, no 8, 5413-22 p.Article in journal (Refereed)
    Abstract [en]

    NF-kappaB transcription factors are involved in evolutionarily conserved signaling pathways controlling multiple cellular processes including apoptosis and immune and inflammatory responses. Immune response of the fruit fly Drosophila melanogaster to Gram-negative bacteria is primarily mediated via the Imd (immune deficiency) pathway, which closely resembles the mammalian TNFR signaling pathway. Instead of cytokines, the main outcome of Imd signaling is the production of antimicrobial peptides. The pathway activity is delicately regulated. Although many of the Imd pathway components are known, the mechanisms of negative regulation are more elusive. In this study we report that a previously uncharacterized gene, pirk, is highly induced upon Gram-negative bacterial infection in Drosophila in vitro and in vivo. pirk encodes a cytoplasmic protein that coimmunoprecipitates with Imd and the cytoplasmic tail of peptidoglycan recognition protein LC (PGRP-LC). RNA interference-mediated down-regulation of Pirk caused Imd pathway hyperactivation upon infection with Gram-negative bacteria, while overexpression of pirk reduced the Imd pathway response both in vitro and in vivo. Furthermore, pirk-overexpressing flies were more susceptible to Gram-negative bacterial infection than wild-type flies. We conclude that Pirk is a negative regulator of the Imd pathway.

  • 26. Kleino, Anni
    et al.
    Valanne, Susanna
    Ulvila, Johanna
    Kallio, Jenni
    Myllymäki, Henna
    Enwald, Heidi
    Stöven, Svenja
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine). Umeå University, Faculty of Medicine, Clinical Microbiology. Umeå University, Faculty of Medicine, Clinical Microbiology, Clinical Bacteriology.
    Poidevin, Mickael
    Ueda, Ryu
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Lemaitre, Bruno
    Rämet, Mika
    Inhibitor of apoptosis 2 and TAK1-binding protein are components of the Drosophila Imd pathway.2005In: EMBO J, ISSN 0261-4189, Vol. 24, no 19, 3423-34 p.Article in journal (Refereed)
    Abstract [en]

    The Imd signaling cascade, similar to the mammalian TNF-receptor pathway, controls antimicrobial peptide expression in Drosophila. We performed a large-scale RNAi screen to identify novel components of the Imd pathway in Drosophila S2 cells. In all, 6713 dsRNAs from an S2 cell-derived cDNA library were analyzed for their effect on Attacin promoter activity in response to Escherichia coli. We identified seven gene products required for the Attacin response in vitro, including two novel Imd pathway components: inhibitor of apoptosis 2 (Iap2) and transforming growth factor-activated kinase 1 (TAK1)-binding protein (TAB). Iap2 is required for antimicrobial peptide response also by the fat body in vivo. Both these factors function downstream of Imd. Neither TAB nor Iap2 is required for Relish cleavage, but may be involved in Relish nuclear localization in vitro, suggesting a novel mode of regulation of the Imd pathway. Our results show that an RNAi-based approach is suitable to identify genes in conserved signaling cascades.

  • 27. Kläger, S L
    et al.
    Watson, A
    Achukwi, D
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Hagen, H E
    Humoral immune response of Simulium damnosum s.l. following filarial and bacterial infections.2002In: Parasitology, ISSN 0031-1820, Vol. 125, no Pt 4, 359-66 p.Article in journal (Refereed)
    Abstract [en]

    The time-course of the humoral immune response of female blackflies after a challenge with bacteria, different Onchocerca microfilariae species, bacterial endotoxin and microfilarial extract was investigated. Strong bacteriolytic and growth inhibition activities against the Gram-positive bacterium Micrococcus luteus were induced by all agents. Specific differences were found in activity levels and time-course. Notably the endotoxin lipopolysaccharide (LPS) induced a very early, profound bacteriolytic and antibacterial response, which declined within a day after injection. In contrast, the bacteriolytic activities after Escherichia coli D31 and Onchocerca microfilariae infections were lower, but remained elevated over the observation period of 4 days. The bacteriolytic activity was correlated to a haemolymph protein with a molecular weight of around 14 kDa. Anti-Gram-positive activity in the E. coli infected group appeared within the first 6 h. However, it took 4 days in the microfilarial infected blackflies to reach significant levels. The active agent was identified to be a peptide with a molecular weight of around 4-4.5 kDa. Activity against the Gram-negative bacteria E. coli was detected in blackflies injected with E. coli D31, O. dukei microfilariae and microfilarial extract on days 1 and 4 after injection. The immune response in S. damnosum s.l. naturally infected via a bloodmeal on cattle supported the findings of the experimental infections. Similarities of the immune response kinetics between bacterial and filarial infections suggested that intracellular Wolbachia bacteria, released from microfilariae, could be responsible for the antibacterial response. This is supported by the observation that the induction of an immune response in the Drosophila melanogaster mbn-2 cell line by the filarial extract is blocked by polymyxin B, which forms inactive complexes with bacterial LPS.

  • 28. Kurucz, Eva
    et al.
    Márkus, Róbert
    Zsámboki, János
    Folkl-Medzihradszky, Katalin
    Darula, Zsuzsanna
    Vilmos, Péter
    Udvardy, Andor
    Krausz, Ildikó
    Lukacsovich, Tamás
    Gateff, Elisabeth
    Zettervall, Carl-Johan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Andó, István
    Nimrod, a putative phagocytosis receptor with EGF repeats in Drosophila plasmatocytes.2007In: Curr Biol, ISSN 0960-9822, Vol. 17, no 7, 649-54 p.Article in journal (Refereed)
    Abstract [en]

    The hemocytes, the blood cells of Drosophila, participate in the humoral and cellular immune defense reactions against microbes and parasites [1-8]. The plasmatocytes, one class of hemocytes, are phagocytically active and play an important role in immunity and development by removing microorganisms as well as apoptotic cells. On the surface of circulating and sessile plasmatocytes, we have now identified a protein, Nimrod C1 (NimC1), which is involved in the phagocytosis of bacteria. Suppression of NimC1 expression in plasmatocytes inhibited the phagocytosis of Staphylococcus aureus. Conversely, overexpression of NimC1 in S2 cells stimulated the phagocytosis of both S. aureus and Escherichia coli. NimC1 is a 90-100 kDa single-pass transmembrane protein with ten characteristic EGF-like repeats (NIM repeats). The nimC1 gene is part of a cluster of ten related nimrod genes at 34E on chromosome 2, and similar clusters of nimrod-like genes are conserved in other insects such as Anopheles and Apis. The Nimrod proteins are related to other putative phagocytosis receptors such as Eater and Draper from D. melanogaster and CED-1 from C. elegans. Together, they form a superfamily that also includes proteins that are encoded in the human genome.

  • 29. Kurucz, Eva
    et al.
    Váczi, B
    Márkus, R
    Laurinyecz, Barbara
    Vilmos, P
    Zsámboki, J
    Csorba, Kinga
    Gateff, Elisabeth
    Hultmark, D
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Andó, I
    Definition of Drosophila hemocyte subsets by cell-type specific antigens.2007In: Acta Biol Hung, ISSN 0236-5383, Vol. 58 Suppl, 95-111 p.Article in journal (Refereed)
    Abstract [en]

    We analyzed the heterogeneity of Drosophila hemocytes on the basis of the expression of cell-type specific antigens. The antigens characterize distinct subsets which partially overlap with those defined by morphological criteria. On the basis of the expression or the lack of expression of blood cell antigens the following hemocyte populations have been defined: crystal cells, plasmatocytes, lamellocytes and precursor cells. The expression of the antigens and thus the different cell types are developmentally regulated. The hemocytes are arranged in four main compartments: the circulating blood cells, the sessile tissue, the lymph glands and the posterior hematopoietic tissue. Each hemocyte compartment has a specific and characteristic composition of the various cell types. The described markers represent the first successful attempt to define hemocyte lineages by immunological markers in Drosophila and help to define morphologically, functionally, spatially and developmentally distinct subsets of hemocytes.

  • 30.
    Kurucz, Eva
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Zettervall, Carl-Johan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Sinka, Rita
    Vilmos, Peter
    Pivarcsi, Andor
    Ekengren, Sophia
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Hegedüs, Zoltán
    Ando, Istvan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Hemese, a hemocyte-specific transmembrane protein, affects the cellular immune response in Drosophila.2003In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 100, no 5, 2622-7 p.Article in journal (Refereed)
    Abstract [en]

    We have identified a previously undescribed transmembrane protein, Hemese, from Drosophila melanogaster blood cells (hemocytes), by using a monoclonal pan-hemocyte antibody. Heavy glycosylation is suggested by the heterogeneous size distribution, ranging between 37 and 70 kDa. Hemese expression is restricted to the cell surfaces of hemocytes of all classes, and to the hematopoietic organs. The sequence of the corresponding gene, Hemese (He), predicts a glycophorin-like protein of 15 kDa, excluding an N-terminal signal peptide, with a single hydrophobic transmembrane region. The extracellular region consists mainly of Ser/Thr-rich sequence of low complexity, with several potential O-glycosylation sites. Hemese contains phosphotyrosine and the cytoplasmic region has potential phosphorylation sites, suggesting an involvement in signal transduction. Depletion of Hemese by RNA interference has no obvious effect under normal conditions, but the cellular response to parasitic wasps is much enhanced. This finding indicates that Hemese plays a modulatory role in the activation or recruitment of the hemocytes.

  • 31. Lindmark, H
    et al.
    Johansson, K C
    Stöven, Svenja
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine). Umeå University, Faculty of Medicine, Clinical Microbiology. Umeå University, Faculty of Medicine, Clinical Microbiology, Clinical Bacteriology.
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Engström, Ylva
    Söderhäll, Kenneth
    Enteric bacteria counteract lipopolysaccharide induction of antimicrobial peptide genes.2001In: J Immunol, ISSN 0022-1767, Vol. 167, no 12, 6920-3 p.Article in journal (Refereed)
    Abstract [en]

    The humoral immunity of Drosophila involves the production of antimicrobial peptides, which are induced by evolutionary conserved microbial molecules, like LPS. By using Drosophila mbn-2 cells, we found that live bacteria, including E. coli, Salmonella typhimurium, Erwinia carotovora, and Pseudomonas aeruginosa, prevented LPS from inducing antimicrobial peptide genes, while Micrococcus luteus and Streptococcus equi did not. The inhibitory effect was seen at bacterial levels from 20 per mbn-2 cell, while antimicrobial peptides were induced at lower bacterial concentrations (< or =2 bacteria per cell) also in the absence of added LPS. Gel shift experiment suggests that the inhibitory effect is upstream or at the level of the activation of the transcription factor Relish, a member of the NF-kappaB/Rel family. The bacteria have to be in physical contact with the cells, but not phagocytosed, to prevent LPS induction. Interestingly, the inhibiting mechanism is, at least for E. coli, independent of the type III secretion system, indicating that the inhibitory mechanism is unrelated to the one earlier described for YopJ from Yersinia.

  • 32. Little, Tom J
    et al.
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Read, Andrew F
    Invertebrate immunity and the limits of mechanistic immunology.2005In: Nat Immunol, ISSN 1529-2908, Vol. 6, no 7, 651-4 p.Article in journal (Refereed)
    Abstract [en]

    Rapid progress is being made in elucidating the molecular mechanisms involved in invertebrate immunity. This search for molecules runs the risk of missing important phenomena. In vertebrates, acquired protection and pathogen-specific responses were demonstrated experimentally long before the mechanisms responsible were elucidated. Without analogous experiments, mechanism-driven work may not demonstrate the full richness of invertebrate immunity.

  • 33. Márkus, Róbert
    et al.
    Laurinyecz, Barbara
    Kurucz, Eva
    Honti, Viktor
    Bajusz, Izabella
    Sipos, Botond
    Somogyi, Kálmán
    Kronhamn, Jesper
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Andó, István
    Sessile hemocytes as a hematopoietic compartment in Drosophila melanogaster2009In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, no 12, 4805-4809 p.Article in journal (Refereed)
    Abstract [en]

    The blood cells, or hemocytes, in Drosophila participate in the immune response through the production of antimicrobial peptides, the phagocytosis of bacteria, and the encapsulation of larger foreign particles such as parasitic eggs; these immune reactions are mediated by phylogenetically conserved mechanisms. The encapsulation reaction is analogous to the formation of granuloma in vertebrates, and is mediated by large specialized cells, the lamellocytes. The origin of the lamellocytes has not been formally established, although it has been suggested that they are derived from the lymph gland, which is generally considered to be the main hematopoietic organ in the Drosophila larva. However, it was recently observed that a subepidermal population of sessile blood cells is released into the circulation in response to a parasitoid wasp infection. We set out to analyze this phenomenon systematically. As a result, we define the sessile hemocytes as a novel hematopoietic compartment, and the main source of lamellocytes.

  • 34.
    Pokrzywa, Malgorzata
    et al.
    Umeå University, Faculty of Medicine, Molecular Biology (Faculty of Medicine).
    Cantera, Rafael
    Dacklin, Ingrid
    Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Vestling, Monika
    Hultmark, Dan
    Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Ultrastructural studies of mutant human transthyretin aggregates in transgenic Drosophila melanogaster2006In: J. Neurogenet., Vol. 20, no 3-4, 203-204 p.Article in journal (Other academic)
  • 35.
    Pokrzywa, Malgorzata
    et al.
    Umeå University, Faculty of Medicine, Molecular Biology (Faculty of Medicine).
    Dacklin, Ingrid
    Umeå University, Faculty of Medicine, Molecular Biology (Faculty of Medicine).
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Lundgren, Erik
    Umeå University, Faculty of Medicine, Molecular Biology (Faculty of Medicine).
    Misfolded transthyretin causes behavioral changes in a Drosophila model for transthyretin-associated amyloidosis.2007In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 26, no 4, 913-924 p.Article in journal (Refereed)
    Abstract [en]

    Familial amyloidotic polyneuropathy is an autosomal dominant neurodegenerative disorder caused by accumulation of mutated transthyretin (TTR) amyloid fibrils in different organs and prevalently around peripheral nerves. We have constructed transgenic flies, expressing the clinical amyloidogenic variant TTRL55P and the engineered variant TTR-A (TTRV14N/V16E) as well as the wild-type protein, all in secreted form. Within a few weeks, both mutants but not the wild-type TTR demonstrated a time-dependent aggregation of misfolded molecules. This was associated with neurodegeneration, change in wing posture, attenuation of locomotor activity including compromised flying ability and shortened life span. In contrast, expression of wild-type TTR had no discernible effect on either longevity or behavior. These results suggest that Drosophila can be used as a disease-model to study TTR amyloid formation, and to screen for pharmacological agents and modifying genes.

  • 36.
    Pokrzywa, Malgorzata
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Dacklin, Ingrid
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Vestling, Monika
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Lundgren, Erik
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Cantera, Rafael
    Department of Zoology, Stockholm University, Stockholm, Sweden.
    Uptake of aggregating transthyretin by fat body in a drosophila model for TTR-associated amyloidosis2010In: PloS one, ISSN 1932-6203, Vol. 5, no 12, e14343- p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: A functional link has been established between the severe neurodegenerative disorder Familial amyloidotic polyneuropathy and the enhanced propensity of the plasma protein transthyretin (TTR) to form aggregates in patients with single point mutations in the TTR gene. Previous work has led to the establishment of an experimental model based on transgenic expression of normal or mutant forms of human TTR in Drosophila flies. Remarkably, the severity of the phenotype was greater in flies that expressed a single copy than with two copies of the mutated gene.

    METHODOLOGY/PRINCIPAL FINDINGS: In this study, we analyze the distribution of normal and mutant TTR in transgenic flies, and the ultrastructure of TTR-positive tissues to clarify if aggregates and/or amyloid filaments are formed. We report the formation of intracellular aggregates of 20 nm spherules and amyloid filaments in thoracic adipose tissue and in brain glia, two tissues that do not express the transgene. The formation of aggregates of nanospherules increased with age and was more considerable in flies with two copies of mutated TTR. Treatment of human neuronal cells with protein extracts prepared from TTR flies of different age showed that the extracts from older flies were less toxic than those from younger flies.

    CONCLUSIONS/SIGNIFICANCE: These findings suggest that the uptake of TTR from the circulation and its subsequent segregation into cytoplasmic quasi-crystalline arrays of nanospherules is part of a mechanism that neutralizes the toxic effect of TTR.

  • 37. Richards, Stephen
    et al.
    Gibbs, Richard A
    Weinstock, George M
    Brown, Susan J
    Denell, Robin
    Beeman, Richard W
    Gibbs, Richard
    Beeman, Richard W
    Brown, Susan J
    Bucher, Gregor
    Friedrich, Markus
    Grimmelikhuijzen, Cornelis J P
    Klingler, Martin
    Lorenzen, Marce
    Richards, Stephen
    Roth, Siegfried
    Schröder, Reinhard
    Tautz, Diethard
    Zdobnov, Evgeny M
    Muzny, Donna
    Gibbs, Richard A
    Weinstock, George M
    Attaway, Tony
    Bell, Stephanie
    Buhay, Christian J
    Chandrabose, Mimi N
    Chavez, Dean
    Clerk-Blankenburg, Kerstin P
    Cree, Andrew
    Dao, Marvin
    Davis, Clay
    Chacko, Joseph
    Dinh, Huyen
    Dugan-Rocha, Shannon
    Fowler, Gerald
    Garner, Toni T
    Garnes, Jeffrey
    Gnirke, Andreas
    Hawes, Alica
    Hernandez, Judith
    Hines, Sandra
    Holder, Michael
    Hume, Jennifer
    Jhangiani, Shalini N
    Joshi, Vandita
    Khan, Ziad Mohid
    Jackson, LaRonda
    Kovar, Christie
    Kowis, Andrea
    Lee, Sandra
    Lewis, Lora R
    Margolis, Jon
    Morgan, Margaret
    Nazareth, Lynne V
    Nguyen, Ngoc
    Okwuonu, Geoffrey
    Parker, David
    Richards, Stephen
    Ruiz, San-Juana
    Santibanez, Jireh
    Savard, Joël
    Scherer, Steven E
    Schneider, Brian
    Sodergren, Erica
    Tautz, Diethard
    Vattahil, Selina
    Villasana, Donna
    White, Courtney S
    Wright, Rita
    Park, Yoonseong
    Beeman, Richard W
    Lord, Jeff
    Oppert, Brenda
    Lorenzen, Marce
    Brown, Susan
    Wang, Liangjiang
    Savard, Joël
    Tautz, Diethard
    Richards, Stephen
    Weinstock, George
    Gibbs, Richard A
    Liu, Yue
    Worley, Kim
    Weinstock, George
    Elsik, Christine G
    Reese, Justin T
    Elhaik, Eran
    Landan, Giddy
    Graur, Dan
    Arensburger, Peter
    Atkinson, Peter
    Beeman, Richard W
    Beidler, Jim
    Brown, Susan J
    Demuth, Jeffery P
    Drury, Douglas W
    Du, Yu-Zhou
    Fujiwara, Haruhiko
    Lorenzen, Marce
    Maselli, Vincenza
    Osanai, Mizuko
    Park, Yoonseong
    Robertson, Hugh M
    Tu, Zhijian
    Wang, Jian-jun
    Wang, Suzhi
    Richards, Stephen
    Song, Henry
    Zhang, Lan
    Sodergren, Erica
    Werner, Doreen
    Stanke, Mario
    Morgenstern, Burkhard
    Solovyev, Victor
    Kosarev, Peter
    Brown, Garth
    Chen, Hsiu-Chuan
    Ermolaeva, Olga
    Hlavina, Wratko
    Kapustin, Yuri
    Kiryutin, Boris
    Kitts, Paul
    Maglott, Donna
    Pruitt, Kim
    Sapojnikov, Victor
    Souvorov, Alexandre
    Mackey, Aaron J
    Waterhouse, Robert M
    Wyder, Stefan
    Zdobnov, Evgeny M
    Zdobnov, Evgeny M
    Wyder, Stefan
    Kriventseva, Evgenia V
    Kadowaki, Tatsuhiko
    Bork, Peer
    Aranda, Manuel
    Bao, Riyue
    Beermann, Anke
    Berns, Nicola
    Bolognesi, Renata
    Bonneton, François
    Bopp, Daniel
    Brown, Susan J
    Bucher, Gregor
    Butts, Thomas
    Chaumot, Arnaud
    Denell, Robin E
    Ferrier, David E K
    Friedrich, Markus
    Gordon, Cassondra M
    Jindra, Marek
    Klingler, Martin
    Lan, Que
    Lattorff, H Michael G
    Laudet, Vincent
    von Levetsow, Cornelia
    Liu, Zhenyi
    Lutz, Rebekka
    Lynch, Jeremy A
    da Fonseca, Rodrigo Nunes
    Posnien, Nico
    Reuter, Rolf
    Roth, Siegfried
    Savard, Joël
    Schinko, Johannes B
    Schmitt, Christian
    Schoppmeier, Michael
    Schröder, Reinhard
    Shippy, Teresa D
    Simonnet, Franck
    Marques-Souza, Henrique
    Tautz, Diethard
    Tomoyasu, Yoshinori
    Trauner, Jochen
    Van der Zee, Maurijn
    Vervoort, Michel
    Wittkopp, Nadine
    Wimmer, Ernst A
    Yang, Xiaoyun
    Jones, Andrew K
    Sattelle, David B
    Ebert, Paul R
    Nelson, David
    Scott, Jeffrey G
    Beeman, Richard W
    Muthukrishnan, Subbaratnam
    Kramer, Karl J
    Arakane, Yasuyuki
    Beeman, Richard W
    Zhu, Qingsong
    Hogenkamp, David
    Dixit, Radhika
    Oppert, Brenda
    Jiang, Haobo
    Zou, Zhen
    Marshall, Jeremy
    Elpidina, Elena
    Vinokurov, Konstantin
    Oppert, Cris
    Zou, Zhen
    Evans, Jay
    Lu, Zhiqiang
    Zhao, Picheng
    Sumathipala, Niranji
    Altincicek, Boran
    Vilcinskas, Andreas
    Williams, Michael
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Hetru, Charles
    Jiang, Haobo
    Grimmelikhuijzen, Cornelis J P
    Hauser, Frank
    Cazzamali, Giuseppe
    Williamson, Michael
    Park, Yoonseong
    Li, Bin
    Tanaka, Yoshiaki
    Predel, Reinhard
    Neupert, Susanne
    Schachtner, Joachim
    Verleyen, Peter
    Raible, Florian
    Bork, Peer
    Friedrich, Markus
    Walden, Kimberly K O
    Robertson, Hugh M
    Angeli, Sergio
    Forêt, Sylvain
    Bucher, Gregor
    Schuetz, Stefan
    Maleszka, Ryszard
    Wimmer, Ernst A
    Beeman, Richard W
    Lorenzen, Marce
    Tomoyasu, Yoshinori
    Miller, Sherry C
    Grossmann, Daniela
    Bucher, Gregor
    The genome of the model beetle and pest Tribolium castaneum.2008In: Nature, ISSN 1476-4687, Vol. 452, no 7190, 949-55 p.Article in journal (Refereed)
    Abstract [en]

    Tribolium castaneum is a representative of earth’s most numerous eukaryotic order, a powerful model organism for the study of generalized insect development, and also an important pest of stored agricultural products. We describe its genome sequence here. This omnivorous beetle has evolved an ability to interact with a diverse chemical environment as evidenced by large expansions in odorant and gustatory receptors, as well as p450 and other detoxification enzymes. Developmental patterns in Tribolium are more representative of other arthropods than those found in Drosophila, a fact represented in gene content and function. For one, Tribolium has retained more ancestral genes involved in cell-cell communication than Drosophila, and some are expressed in the growth zone crucial for axial elongation in short germ development. Systemic RNAi in T. castaneum appears to use mechanisms distinct from those found in C. elegans, but nevertheless offers similar power for the elucidation of gene function and identification of targets for selective insect control.

  • 38. Rus, Florentina
    et al.
    Kurucz, Eva
    Márkus, Róbert
    Sinenko, Sergey A
    Laurinyecz, Barbara
    Pataki, Csilla
    Gausz, János
    Hegedus, Zoltán
    Udvardy, Andor
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Andó, István
    Expression pattern of Filamin-240 in Drosophila blood cells.2006In: Gene Expr Patterns, ISSN 1567-133X, Vol. 6, no 8, 928-34 p.Article in journal (Refereed)
    Abstract [en]

    The expression pattern of Filamin-240 was studied in subsets of Drosophila blood cells by means of immunofluorescent staining and Western blot analysis with use of an antibody specific to a &quot;filamin-folding domain&quot;, a consensus motif profile generated from the 20 existing filamin repeats. Expression of Filamin-240 is restricted to lamellocytes - a special blood cell type of the cellular immune response - and is involved in the regulation of lamellocyte development. In the cher1 homozygous larvae, which lack Filamin-240 protein, a vigorous lamellocyte differentiation occurs which is further enhanced upon in vivo immune challenge by a parasitic wasp, Leptopilina boulardi. By introducing a full-length transgene encoding the Drosophila Filamin-240 protein into the cher1 Filamin-deficient homozygous mutant, the mutant blood cell phenotype was rescued. These data demonstrate that the expression of Filamin-240 is strictly lamellocyte specific in Drosophila blood cells and that the protein is a suppressor of lamellocyte development.

  • 39. Sackton, Timothy B
    et al.
    Lazzaro, Brian P
    Schlenke, Todd A
    Evans, Jay D
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Clark, Andrew G
    Dynamic evolution of the innate immune system in Drosophila.2007In: Nat Genet, ISSN 1061-4036, Vol. 39, no 12, 1461-8 p.Article in journal (Refereed)
    Abstract [en]

    The availability of complete genome sequence from 12 Drosophila species presents the opportunity to examine how natural selection has affected patterns of gene family evolution and sequence divergence among different components of the innate immune system. We have identified orthologs and paralogs of 245 Drosophila melanogaster immune-related genes in these recently sequenced genomes. Genes encoding effector proteins, and to a lesser extent genes encoding recognition proteins, are much more likely to vary in copy number across species than genes encoding signaling proteins. Furthermore, we can trace the apparent recent origination of several evolutionarily novel immune-related genes and gene families. Using codon-based likelihood methods, we show that immune-system genes, and especially those encoding recognition proteins, evolve under positive darwinian selection. Positively selected sites within recognition proteins cluster in domains involved in recognition of microorganisms, suggesting that molecular interactions between hosts and pathogens may drive adaptive evolution in the Drosophila immune system.

  • 40. Sampson, Christopher J
    et al.
    Valanne, Susanna
    Fauvarque, Marie-Odile
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Rämet, Mika
    Williams, Michael J
    The RhoGEF Zizimin-related acts in the Drosophila cellular immune response via the Rho GTPases Rac2 and Cdc422012In: Developmental and Comparative Immunology, ISSN 0145-305X, E-ISSN 1879-0089, Vol. 38, no 1, 160-168 p.Article in journal (Refereed)
    Abstract [en]

    Zizimin-related (Zir), a Rho guanine nucleotide exchange factor (RhoGEF) homologous to the mammalian Dock-C/Zizimin-related family, was identified in a screen to find new genes involved in the Drosophila melanogaster cellular immune response against eggs from the parasitoid wasp Leptopilina boulardi. RhoGEFs activate Rho-family GTPases, which are known to be central regulators of cell migration, spreading and polarity. When a parasitoid wasp is recognized as foreign, multiple layers of circulating immunosurveillance cells (haemocytes) should attach to the egg. In Zir mutants this process is disrupted and lamellocytes, a haemocyte subtype, fail to properly encapsulate the wasp egg. Furthermore, macrophage-like plasmatocytes exhibit a strong reduction in their ability to phagocytise Escherichia coli and Staphylococcus aureus bacteria. During encapsulation and phagocytosis Zir genetically interacts with two Rho-family GTPases, Rac2 and Cdc42. Finally, Zir is dispensable for the humoral immune response against bacteria. We propose that Zir is necessary to activate the Rho-family GTPases Rac2 and Cdc42 during the Drosophila cellular immune response.

  • 41.
    Schmid, Martin R
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Anderl, Ines
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Valanne, S
    Vo, H
    Yang, Hairu
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Kronhamn, J
    Rusten, TE
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Genetic screen in Drosophila larvae links ird1 function to Toll signaling in the fat body and hemocyte motilityManuscript (preprint) (Other academic)
  • 42.
    Schmid, Martin Rudolf
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Anderl, Ines
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Institute of Biomedical Technology (BioMediTech), University of Tampere, Tampere, Finland.
    Vesala, L
    Vanha-aho, L-M
    Deng, Xiao-Juan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). College of Animal Science, South China Agricultural University, Guangzhou, China.
    Rämet, M
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Institute of Biomedical Technology (BioMediTech), University of Tampere, Tampere, Finland.
    Control of Drosophila blood cell activation via toll signaling in the fat body2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 8, e102568Article in journal (Refereed)
    Abstract [en]

    The Toll signaling pathway, first discovered in Drosophila, has a well-established role in immune responses in insects as well as in mammals. In Drosophila, the Toll-dependent induction of antimicrobial peptide production has been intensely studied as a model for innate immune responses in general. Besides this humoral immune response, Toll signaling is also known to activate blood cells in a reaction that is similar to the cellular immune response to parasite infections, but the mechanisms of this response are poorly understood. Here we have studied this response in detail, and found that Toll signaling in several different tissues can activate a cellular immune defense, and that this response does not require Toll signaling in the blood cells themselves. Like in the humoral immune response, we show that Toll signaling in the fat body (analogous to the liver in vertebrates) is of major importance in the Toll-dependent activation of blood cells. However, this Toll-dependent mechanism of blood cell activation contributes very little to the immune response against the parasitoid wasp, Leptopilina boulardi, probably because the wasp is able to suppress Toll induction. Other redundant pathways may be more important in the defense against this pathogen.

  • 43. Silverman, N
    et al.
    Zhou, R
    Stöven, Svenja
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine). Umeå University, Faculty of Medicine, Clinical Microbiology. Umeå University, Faculty of Medicine, Clinical Microbiology, Clinical Bacteriology.
    Pandey, N
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Maniatis, T
    A Drosophila IkappaB kinase complex required for Relish cleavage and antibacterial immunity.2000In: Genes Dev, ISSN 0890-9369, Vol. 14, no 19, 2461-71 p.Article in journal (Refereed)
    Abstract [en]

    Here we report the identification of a Drosophila IkappaB kinase complex containing DmIKKbeta and DmIKKgamma, homologs of the human IKKbeta and IKKgamma proteins. We show that this complex is required for the signal-dependent cleavage of Relish, a member of the Rel family of transcriptional activator proteins, and for the activation of antibacterial immune response genes. In addition, we find that the activated DmIKK complex, as well as recombinant DmIKKbeta, can phosphorylate Relish in vitro. Thus, we propose that the Drosophila IkappaB kinase complex functions, at least in part, by inducing the proteolytic cleavage of Relish. The N terminus of Relish then translocates to the nucleus and activates the transcription of antibacterial immune response genes. Remarkably, this Drosophila IkappaB kinase complex is not required for the activation of the Rel proteins Dif and Dorsal through the Toll signaling pathway, which is essential for antifungal immunity and dorsoventral patterning during early development. Thus, a yet to be identified IkappaB kinase complex must be required for Rel protein activation via the Toll signaling pathway.

  • 44. Somogyi, Kálmán
    et al.
    Sipos, Botond
    Pénzes, Zsolt
    Kurucz, Eva
    Zsámboki, János
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Andó, István
    Evolution of genes and repeats in the Nimrod superfamily.2008In: Mol Biol Evol, ISSN 1537-1719, Vol. 25, no 11, 2337-47 p.Article in journal (Refereed)
    Abstract [en]

    The recently identified Nimrod superfamily is characterized by the presence of a special type of EGF repeat, the NIM repeat, located right after a typical CCXGY/W amino acid motif. On the basis of structural features, nimrod genes can be divided into three types. The proteins encoded by Draper-type genes have an EMI domain at the N-terminal part and only one copy of the NIM motif, followed by a variable number of EGF-like repeats. The products of Nimrod B-type and Nimrod C-type genes (including the eater gene) have different kinds of N-terminal domains, and lack EGF-like repeats but contain a variable number of NIM repeats. Draper and Nimrod C-type (but not Nimrod B-type) proteins carry a transmembrane domain. Several members of the superfamily were claimed to function as receptors in phagocytosis and/or binding of bacteria, which indicates an important role in the cellular immunity and the elimination of apoptotic cells. In this paper, the evolution of the Nimrod superfamily is studied with various methods on the level of genes and repeats. A hypothesis is presented in which the NIM repeat, along with the EMI domain, emerged by structural reorganizations at the end of an EGF-like repeat chain, suggesting a mechanism for the formation of novel types of repeats. The analyses revealed diverse evolutionary patterns in the sequences containing multiple NIM repeats. Although in the Nimrod B and Nimrod C proteins show characteristics of independent evolution, many internal NIM repeats in Eater sequences seem to have undergone concerted evolution. An analysis of the nimrod genes has been performed using phylogenetic and other methods and an evolutionary scenario of the origin and diversification of the Nimrod superfamily is proposed. Our study presents an intriguing example how the evolution of multigene families may contribute to the complexity of the innate immune response.

  • 45. Steiner, Håkan
    et al.
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Engström, Åke
    Bennich, Hans
    Boman, Hans G
    Sequence and specificity of two antibacterial proteins involved in insect immunity. Nature 292: 246-248. 1981.2009In: Journal of immunology (Baltimore, Md. : 1950), ISSN 1550-6606, Vol. 182, no 11, 6635-7 p.Article in journal (Refereed)
    Abstract [en]

    Immune responses have been described for many different insect species. However, it is generally acknowledged that immune systems must therefore differ from those of vertebrates. An effective humoral immune response has been found in pupae of the cecropia moth, Hyalophora cecropia. The expression of this multicomponent system requires de novo synthesis of RNA and proteins and its broad antibacterial activity is due to at least three independent mechanisms, the most well known of which is the insect lysozyme. However, this enzyme is bactericidal for only a limited number of Gram-positive bacteria. WE recently purified and characterized P9A and P9B, which are two small, basic proteins with potent antibacterial activity against Escherichia coli and several other Gram-negative bacteria. We believe that P9A and P9B plays an important part in the humoral immune responses described previously and that the P9 proteins represent a new class of antibacterial agents for which we propose the name cecropins. We describe here the primary structures of cecropins A and B. We also show that cecropin A is specific for bacteria in contrast to melittin, the main lytic component in bee venom which lyses both bacteria and eukaryotic cells.

  • 46.
    Stöven, Svenja
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine). Umeå University, Faculty of Medicine, Clinical Microbiology, Clinical Bacteriology.
    Ando, Istvan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Kadalayil, Latha
    Engström, Ylva
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Activation of the Drosophila NF-kappaB factor Relish by rapid endoproteolytic cleavage.2000In: EMBO Rep, ISSN 1469-221X, Vol. 1, no 4, 347-52 p.Article in journal (Refereed)
    Abstract [en]

    The Rel/NF-kappaB transcription factor Relish plays a key role in the humoral immune response in Drosophila. We now find that activation of this innate immune response is preceded by rapid proteolytic cleavage of Relish into two parts. An N-terminal fragment, containing the DNA-binding Rel homology domain, translocates to the nucleus where it binds to the promoter of the Cecropin A1 gene and probably to the promoters of other antimicrobial peptide genes. The C-terminal IkappaB-like fragment remains in the cytoplasm. This endoproteolytic cleavage does not involve the proteasome, requires the DREDD caspase, and is different from previously described mechanisms for Rel factor activation.

  • 47.
    Stöven, Svenja
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine). Umeå University, Faculty of Medicine, Clinical Microbiology, Clinical Bacteriology.
    Silverman, Neal
    Junell, Anna
    Hedengren-Olcott, Marika
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Erturk, Deniz
    Engstrom, Ylva
    Maniatis, Tom
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Caspase-mediated processing of the Drosophila NF-kappaB factor Relish.2003In: Proc Natl Acad Sci U S A, ISSN 0027-8424, Vol. 100, no 10, 5991-6 p.Article in journal (Refereed)
    Abstract [en]

    The NF-kappaB-like transcription factor Relish plays a central role in the innate immune response of Drosophila. Unlike other NF-kappaB proteins, Relish is activated by endoproteolytic cleavage to generate a DNA-binding Rel homology domain and a stable IkappaB-like fragment. This signal-induced endoproteolysis requires the activity of several gene products, including the IkappaB kinase complex and the caspase Dredd. Here we used mutational analysis and protein microsequencing to demonstrate that a caspase target site, located in the linker region between the Rel and the IkappaB-like domain, is the site of signal-dependent cleavage. We also show physical interaction between Relish and Dredd, suggesting that Dredd indeed is the Relish endoprotease. In addition to the caspase target site, the C-terminal 107 aa of Relish are required for endoproteolysis and signal-dependent phosphorylation by the Drosophila IkappaB kinase beta. Finally, an N-terminal serine-rich region in Relish and the PEST domain were found to negatively regulate Relish activation.

  • 48.
    Ulvila, J
    et al.
    Department of Pediatrics, University of Oulu, Oulu, Finland.
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Rämet, M
    Institute of Medical Technology, University of Tampere, Tampere, Finland.
    RNA silencing in the antiviral innate immune defence--role of DEAD-box RNA helicases2010In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 71, no 3, 146-158 p.Article in journal (Refereed)
    Abstract [en]

    RNA silencing is an efficient biochemical tool for gene knock downs as well as physiological phenomenon playing a major role in diverse biological processes. Recent knowledge suggests that the same protein families which mediate the experimental RNA interference (RNAi) in the fruit fly Drosophila melanogaster cells also contribute to the antiviral host defence in both invertebrate model organisms and mammals. Additionally, another branch of RNA silencing, the microRNAs (miRNAs), has been recently described in the context of host defence. In several studies, miRNAs have been shown to regulate essential immune responses. This review summarizes basic concepts of RNAi and miRNAs, especially in the context of immune defence, focusing on the newly discovered role of DEAD-box helicases in the RNA interference and antiviral host defence.

  • 49. Ulvila, Johanna
    et al.
    Vanha-aho, Leena-Maija
    Kleino, Anni
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Vähä-Mäkilä, Mari
    Vuoksio, Milka
    Eskelinen, Sinikka
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Kocks, Christine
    Hallman, Mikko
    Parikka, Mataleena
    Rämet, Mika
    Cofilin regulator 14-3-3zeta is an evolutionarily conserved protein required for phagocytosis and microbial resistance2011In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 89, no 5, 649-659 p.Article in journal (Refereed)
    Abstract [en]

    Phagocytosis is an ancient cellular process that plays an important role in host defense. In Drosophila melanogaster phagocytic, macrophage-like hemocytes recognize and ingest microbes. We performed an RNAi-based in vitro screen in the Drosophila hemocyte cell line S2 and identified Abi, cpa, cofilin regulator 14-3-3ζ, tlk, CG2765, and CG15609 as mediators of bacterial phagocytosis. Of these identified genes, 14-3-3ζ had an evolutionarily conserved role in phagocytosis: bacterial phagocytosis was compromised when 14-3-3ζ was targeted with RNAi in primary Drosophila hemocytes and when the orthologous genes Ywhab and Ywhaz were silenced in zebrafish and mouse RAW 264.7 cells, respectively. In Drosophila and zebrafish infection models, 14-3-3ζ was required for resistance against Staphylococcus aureus. We conclude that 14-3-3ζ is essential for phagocytosis and microbial resistance in insects and vertebrates.

  • 50.
    Valanne, Susanna
    et al.
    University of Tampere.
    Myllymäki, Henna
    Kallio, Jenni
    Schmid, Martin Rudolf
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Kleino, Anni
    University of Tampere.
    Murumägi, Astrid
    Airaksinen, Laura
    Kotipelto, Tapio
    Kaustio, Meri
    Ulvila, Johanna
    Esfahani, Shiva Seyedoleslami
    Engström, Ylva
    Silvennoinen, Olli
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Parikka, Mataleena
    Rämet, Mika
    Genome-wide RNA interference in Drosophila cells identifies G protein-coupled receptor kinase 2 as a conserved regulator of NF-κB signaling2010In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 184, no 11, 6188-6198 p.Article in journal (Refereed)
    Abstract [en]

    Because NF-kappaB signaling pathways are highly conserved in evolution, the fruit fly Drosophila melanogaster provides a good model to study these cascades. We carried out an RNA interference (RNAi)-based genome-wide in vitro reporter assay screen in Drosophila for components of NF-kappaB pathways. We analyzed 16,025 dsRNA-treatments and identified 10 novel NF-kappaB regulators. Of these, nine dsRNA-treatments affect primarily the Toll pathway. G protein-coupled receptor kinase (Gprk)2, CG15737/Toll pathway activation mediating protein, and u-shaped were required for normal Drosomycin response in vivo. Interaction studies revealed that Gprk2 interacts with the Drosophila IkappaB homolog Cactus, but is not required in Cactus degradation, indicating a novel mechanism for NF-kappaB regulation. Morpholino silencing of the zebrafish ortholog of Gprk2 in fish embryos caused impaired cytokine expression after Escherichia coli infection, indicating a conserved role in NF-kappaB signaling. Moreover, small interfering RNA silencing of the human ortholog GRK5 in HeLa cells impaired NF-kappaB reporter activity. Gprk2 RNAi flies are susceptible to infection with Enterococcus faecalis and Gprk2 RNAi rescues Toll(10b)-induced blood cell activation in Drosophila larvae in vivo. We conclude that Gprk2/GRK5 has an evolutionarily conserved role in regulating NF-kappaB signaling.

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